蛋白酶体抑制剂MG-132下调炎症因子表达抑制大鼠心肌再灌注损伤

Proteasome inhibitor MG-132 inhibits myocardial reperfusion injury in rats by suppressing expression of inflammatory factors

目的研究蛋白酶体抑制剂MG-132对大鼠缺血再灌注心肌组织中炎症因子的影响。方法选择92只SD大鼠结扎左冠状动脉前降支30min制作心肌缺血再灌注模型。治疗(I/R+T)组及假手术+治疗(Sham+T)组于再灌注前5min静脉注射蛋白酶体抑制剂MG-1320.75mg/kg,对照(I/R)组及假手术(Sham)组注射与之相同容积的生理盐水。观察I/R组和I/R+T组再灌注0、1、2、6、24h心肌组织超微结构变化,核因子-κBp65(NF-κBp65)、肿瘤坏死因子-α(TNF-α)的mRNA和蛋白质水平,嗜中性白细胞(PMN)计数,髓过氧化物酶活(MPO)性以及各组存活率。结果与Sham组及Sham+T组相比,I/R组的NF-κBp65、TNF-α水平,PMN计数,MPO活性均显著增加(P<0·05)。I/R组中1、2、6、24h组的上述各项炎性指标比0h组显著增高(P<0·05);电镜下观察可见缺血再灌注组弥漫性心肌细胞肿胀、大量肌丝溶解,线粒体肿胀空化。与I/R组相比,I/R+T组心肌细胞损伤程度大大减轻,并显著抑制了炎症因子的表达、嗜中性白细胞的浸润及MPO活性(P<0·05),作用至少维持24h,并使因心律失常死亡减少。结论MG-132通过降低缺血再灌注心肌组织中炎症因子的表达,抑制了再灌注损伤。

Objective To investigate the influence of proteasome inhibitor MG-132 on inflammatory factors in rat model of myocardial ischemia/reperfusion. Methods Adult Sprague-Dawley rats were divided into 4 groups. I/R group： left anterior descending （LAD） coronary artery was ligated for 30 min, and then reperfused for 0, 1, 2, 6, 24 h; I/R ＋ T group： MG-132 was used for treatment, and other procedures as I/R group; Sham operation group; Sham operation ＋ T group. At 5 min before reperfusion, MG-132 （0.75 mg/kg） was given intravenously in I/R ＋ T group and Sham operation ＋ T group, and normal saline for I/R group and sham operation group. The changes of myocardial uhrastructure were checked, and the protein and mRNA levels of NF-KBp65 and TNF-α, the number of PMN, the activity of MPO and survival of each group were detected. ReSUitS As compared with Sham operation group and Sham operation ＋ T group, the protein and mRNA levels of NF-KBp65 and TNF-α, the number of polymorphonuclear leucocytes （PMN） and the activity of myeloperoxidase （MPO） were significantly increased in I/R group （ P 〈 0.05 ） , and these indexes were significantly higher at 1, 2, 6, 24 h after reperfusion than that at 0 h （ P 〈 0. 05 ）. The cardiocytes diffused and swelled, the myofilament was lysed, and the mitochondria swelled and vacuolizated. The above-mentioned inflammatory factors of I/R ＋ T group were significantly decreased as compared with I/R group （ P 〈 0. 05 ）, and could keep at a low level at least for 24 h. The damaged degree of cardiocytes in I/R ＋ T group was less and the mortality due to deadly arrhythmia was lower than that of I/R group. Conclusion Myocardial reperfusion injury can be inhibited by proteasome inhibitor MG-132 through suppressing the expression of inflammatory factor in rats.